chr16-47650919-C-A

Variant names:

• chr16-47650919-C-A
• rs34667348
• NM_000293.3:c.1969C>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000293.3(PHKB):​c.1969C>A​(p.Gln657Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0038 in 1,604,956 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q657H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (15 hom.)
• Consequence: PHKB NM_000293.3 missense, splice_region
• Scores: Splicing: ADA: 0.05761
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:5 O:1
• Conservation: PhyloP100: 7.26

Genes affected

PHKB (HGNC:8927): (phosphorylase kinase regulatory subunit beta) Phosphorylase kinase is a polymer of 16 subunits, four each of alpha, beta, gamma and delta. The alpha subunit includes the skeletal muscle and hepatic isoforms, encoded by two different genes. The beta subunit is the same in both the muscle and hepatic isoforms, encoded by this gene, which is a member of the phosphorylase b kinase regulatory subunit family. The gamma subunit also includes the skeletal muscle and hepatic isoforms, encoded by two different genes. The delta subunit is a calmodulin and can be encoded by three different genes. The gamma subunits contain the active site of the enzyme, whereas the alpha and beta subunits have regulatory functions controlled by phosphorylation. The delta subunit mediates the dependence of the enzyme on calcium concentration. Mutations in this gene cause glycogen storage disease type 9B, also known as phosphorylase kinase deficiency of liver and muscle. Alternatively spliced transcript variants encoding different isoforms have been identified in this gene. Two pseudogenes have been found on chromosomes 14 and 20, respectively.[provided by RefSeq, Feb 2010]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.026981533).
• BP6: Variant 16-47650919-C-A is Benign according to our data. Variant chr16-47650919-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 281127.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, not_provided=1, Likely_benign=4}. Variant chr16-47650919-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00282 (429/152312) while in subpopulation NFE AF = 0.00525 (357/68020). AF 95% confidence interval is 0.0048. There are 2 homozygotes in GnomAd4. There are 185 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHKB	NM_000293.3	c.1969C>A	p.Gln657Lys	missense_variant, splice_region_variant	Exon 20 of 31	ENST00000323584.10	NP_000284.1
PHKB	NM_001363837.1	c.1969C>A	p.Gln657Lys	missense_variant, splice_region_variant	Exon 20 of 31		NP_001350766.1
PHKB	NM_001031835.3	c.1948C>A	p.Gln650Lys	missense_variant, splice_region_variant	Exon 21 of 32		NP_001027005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHKB	ENST00000323584.10	c.1969C>A	p.Gln657Lys	missense_variant, splice_region_variant	Exon 20 of 31	1	NM_000293.3	ENSP00000313504.5

Frequencies

GnomAD3 genomes AF: 0.00282 AC: 429 AN: 152194 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00525

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00276 AC: 694 AN: 251224 AF XY: 0.00291

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00106

Gnomad NFE exome AF: 0.00525

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00390 AC: 5669 AN: 1452644 Hom.: 15 Cov.: 29 AF XY: 0.00379 AC XY: 2740 AN XY: 723288

Gnomad4 AFR exome AF: 0.000721 AC: 24 AN: 33292

Gnomad4 AMR exome AF: 0.00121 AC: 54 AN: 44714

Gnomad4 ASJ exome AF: 0.000192 AC: 5 AN: 26072

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39634

Gnomad4 SAS exome AF: 0.0000697 AC: 6 AN: 86080

Gnomad4 FIN exome AF: 0.00155 AC: 83 AN: 53402

Gnomad4 NFE exome AF: 0.00485 AC: 5352 AN: 1103604

Gnomad4 Remaining exome AF: 0.00218 AC: 131 AN: 60096

GnomAD4 genome AF: 0.00282 AC: 429 AN: 152312 Hom.: 2 Cov.: 32 AF XY: 0.00248 AC XY: 185 AN XY: 74486

Gnomad4 AFR AF: 0.000794 AC: 0.000793765 AN: 0.000793765

Gnomad4 AMR AF: 0.00157 AC: 0.00156904 AN: 0.00156904

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00122 AC: 0.00122411 AN: 0.00122411

Gnomad4 NFE AF: 0.00525 AC: 0.00524846 AN: 0.00524846

Gnomad4 OTH AF: 0.000945 AC: 0.00094518 AN: 0.00094518

Alfa AF: 0.00398 Hom.: 4

Bravo AF: 0.00283

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00453 AC: 39

ExAC AF: 0.00290 AC: 352

EpiCase AF: 0.00387

EpiControl AF: 0.00362

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Glycogen storage disease IXb Uncertain:2 Benign:2 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 05, 2022

MGZ Medical Genetics Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Uncertain:3 Benign:1

Mar 14, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported as a variant of unclear significance in the heterozygous state in an individual with muscle glycogenosis and low phosphorylase kinase activity in whom a second PHKB variant was not identified (Burwinkle et al., 2003); Identified in a patient with myopathy and limb-girdle weakness with a second variant in PHKB, as well as variants in other genes but segregation information and in vitro functional studies were not included (Rotwein et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24082139, 28146470, 12825073, 29970176) -

Jun 03, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PHKB: BS2 -

Aug 31, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1 -

not specified Benign:1

Oct 13, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PHKB c.1969C>A (p.Gln657Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0028 in 251224 control chromosomes, predominantly at a frequency of 0.0052 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in PHKB causing Glycogen Phosphorylase Kinase Deficiency phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1969C>A has been reported in the literature in individuals affected with Glycogen Phosphorylase Kinase Deficiency or Limb girdle muscular dystrophies (Burwinkel_2003, Fichna_2018). These reports do not provide unequivocal conclusions about association of the variant with Glycogen Phosphorylase Kinase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17689125, 12825073, 29970176, 24082139, 28146470, 31214250). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=6) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign. -

PHKB-related disorder Benign:1

Feb 09, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	.;.;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.027	T;T;T
MetaSVM	Uncertain	0.42	D
MutationAssessor	Benign	1.7	.;L;L
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0070	D;D;D
Sift4G	Uncertain	0.016	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.76
MVP		0.91
MPC		0.63
ClinPred		0.017	T
GERP RS		4.8
Varity_R		0.61
gMVP		0.83
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.058
dbscSNV1_RF	Benign	0.36
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs34667348; hg19: chr16-47684830;